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Background Lesbian, gay, bisexual and transgender (LGBT) patients have an increased incidence of a range of health problems, and face many barriers to accessing healthcare. Our research aimed to explore the awareness of health issues and attitudes of medical students towards LGBT patients’ health including barriers to health services, their attitudes towards inclusion of LGBT content in the curriculum and their confidence with providing care for their LGBT patients in the future. Methods Medical students were recruited to take part in a cross-sectional survey. We used a 28-item survey to explore views about the undergraduate medical curriculum. Results 252 surveys were analysed from 776 eligible participants. Attitudes towards LGBT patients were positive but awareness and confidence with respect to LGBT patients were variable. Confidence discussing sexual orientation with a patient significantly increased with year of study but confidence discussing patient gender identity did not. The majority of participants ( n  = 160; 69%) had not received specific training on LGBT health needs, and 85% ( n  = 197) wanted to receive more training. Conclusions Increasing the amount of LGBT teaching in undergraduate medical curricula could help to increase the quality of doctor-patient interactions, to facilitate patients’ disclosure of sexual orientation and gender identity in healthcare and increase the quality of healthcare.

Human embryonic stem cells (hESCs) hold potential in the field of tissue engineering to treat a wide range of diseases, given their capacity for both limitless self-renewal and differentiation to any somatic cell type. However, under standard culture conditions, hESCs have a tendency to spontaneously differentiate. Thus, research is required to understand the mechanisms that regulate stem cell self-renewal and the impact on hESC culture. Human embryonal teratocarcinoma cells (hECCs), the malignant counterparts of hESCs, are also pluripotent, proliferate by self-renewal, and provide a convenient alternative model to study the regulation of pluripotency. Accumulating evidence suggests that glycolysis and hypoxia, through the hypoxia inducible factor HIF-2α, are key regulators of hESC self-renewal, but how changes in metabolism affect gene expression is poorly understood. The aim of this study was to determine how glycolysis affected the epigenetic and metabolic regulation of hESC self-renewal maintenance under hypoxia. Chromatin immunoprecipitation (ChIP) analysis showed that HIF-2α directly binds to a HRE site in the proximal promoters of the metabolic sensors CtBPs, which link the metabolic state of the cell to changes in gene expression. HIF-2α was also demonstrated to regulate the expression of the chromatin modifiers JMJDs in hESCs under hypoxia, except for JMJD2c. JMJD2c expression peaked within the first 48 hours of exposure to hypoxia and thus was regulated instead by HIF-1α. Inhibiting glycolysis with the addition of glycolytic inhibitors revealed a consequential decrease in JMJD, CtBP and pluripotency marker expression, but intriguingly also HIF-2α, in hESCs maintained under hypoxia by inducing a more heterochromatic state in the proximal promoters of key genes. ChIP analysis revealed that JMJD2a plays a role in hESC self-renewal by inducing a more euchromatic and accessible state around the HREs in the proximal promoters of OCT4, SOX2 and NANOG by removing H3K9me3 histone modifications. CtBPs were also demonstrated to have a role in hESC selfrenewal by acting as a transcriptional coactivator. Furthermore, the mechanisms regulating hESC self-renewal were compared to those in the malignant counterparts, hECCs. All mechanisms analysed were similar between the two cell types, except that pluripotency marker expression was not regulated by environmental oxygen in hECCs. Both HIF-1α and HIF-2α were expressed in hECCs maintained at 20% oxygen, and HIF-α subunit accumulation was caused by high levels of nitric oxide preventing HIF degradation by PHDs. The data presented in this thesis has identified several mechanisms that enhance self-renewal including hypoxia, metabolic sensors, epigenetics, nitric oxide and most importantly glycolysis. Together, these data have uncovered a potential insight into how hESCs first adapt to hypoxia, but also mechanisms into how that cell identity is maintained and enhanced under long-term hypoxia. However, crucially, glycolysis appears to not be just a feature of pluripotency, but is intrinsic to the acquisition and maintenance of self-renewal.

\"BUSH is now a suburb: 600 homes in seven years\" reads an article from the Newcastle Herald in 1965. The story speaks of a Newcastle suburb in the making -...

In cnidarian-Symbiodiniaceae symbioses, algal endosymbiont population control within the host is needed to sustain a symbiotic relationship. However, the molecular mechanisms that underlie such population control are unclear. Here we show that a cnidarian host uses nitrogen limitation as a primary mechanism to control endosymbiont populations. Nitrogen acquisition and assimilation transcripts become elevated in symbiotic Breviolum minutum algae as they reach high-densities within the sea anemone host Exaiptasia pallida . These same transcripts increase in free-living algae deprived of nitrogen. Symbiotic algae also have an elevated carbon-to-nitrogen ratio and shift metabolism towards scavenging nitrogen from purines relative to free-living algae. Exaiptasia glutamine synthetase and glutamate synthase transcripts concomitantly increase with the algal endosymbiont population, suggesting an increased ability of the host to assimilate ammonium. These results suggest algal growth and replication in hospite is controlled by access to nitrogen, which becomes limiting for the algae as their population within the host increases. The relationship between the coral animal and symbiotic algae is essential to coral health, and researchers are turning to Exaiptasia , a model cnidarian system, to study this relationship mechanistically. Here the authors find that endosymbiotic algae become limited by nitrogen at high population densities and provide the host with high levels of fixed carbon.

Segmentation and detection of biological objects in fluorescence microscopy is of paramount importance in cell imaging. Deep learning approaches have recently shown promise to advance, automatize and accelerate analysis. However, most of the interest has been given to the segmentation of static objects of 2D/3D images whereas the segmentation of dynamic processes obtained from time-lapse acquisitions has been less explored. Here we adapted DeepFinder, a U-Net originally designed for 3D noisy cryo-electron tomography (cryo-ET) data, for the detection of rare dynamic exocytosis events (termed ExoDeepFinder) observed in temporal series of 2D Total Internal Reflection Fluorescence Microscopy (TIRFM) images. ExoDeepFinder achieved good absolute performances with a relatively small training dataset of 12000 events in 60 cells. We rigorously compared deep learning performances with unsupervised conventional methods from the literature. ExoDeepFinder outcompeted the tested methods, but also exhibited a greater plasticity to the experimental conditions when tested under drug treatments and after changes in cell line or imaged reporter. This robustness to unseen experimental conditions did not require re-training demonstrating generalization capability of our deep learning model. ExoDeepFinder, as well as the annotated training datasets, were made transparent and available through an open-source software as well as a Napari plugin and can directly be applied to custom user data. The apparent plasticity and performances of ExoDeepFinder to detect dynamic events open new opportunities for future deep learning guided analysis of dynamic processes in live-cell imaging.

The choroid plexus epithelium (CPE) is a lobed neuro-epithelial structure that forms the outer blood-brain barrier. The CPE protrudes into the brain ventricles and produces the cerebrospinal fluid (CSF), which is crucial for brain homeostasis. Malfunction of the CPE is possibly implicated in disorders like Alzheimer disease, hydrocephalus or glaucoma. To study human genetic diseases and potential new therapies, mouse models are widely used. This requires a detailed knowledge of similarities and differences in gene expression and functional annotation between the species. The aim of this study is to analyze and compare gene expression and functional annotation of healthy human and mouse CPE. We performed 44k Agilent microarray hybridizations with RNA derived from laser dissected healthy human and mouse CPE cells. We functionally annotated and compared the gene expression data of human and mouse CPE using the knowledge database Ingenuity. We searched for common and species specific gene expression patterns and function between human and mouse CPE. We also made a comparison with previously published CPE human and mouse gene expression data. Overall, the human and mouse CPE transcriptomes are very similar. Their major functionalities included epithelial junctions, transport, energy production, neuro-endocrine signaling, as well as immunological, neurological and hematological functions and disorders. The mouse CPE presented two additional functions not found in the human CPE: carbohydrate metabolism and a more extensive list of (neural) developmental functions. We found three genes specifically expressed in the mouse CPE compared to human CPE, being ACE, PON1 and TRIM3 and no human specifically expressed CPE genes compared to mouse CPE. Human and mouse CPE transcriptomes are very similar, and display many common functionalities. Nonetheless, we also identified a few genes and pathways which suggest that the CPE between mouse and man differ with respect to transport and metabolic functions.

Increasing evidence implicates the tumor microbiota as a factor that can influence cancer progression. In patients with colorectal cancer (CRC), we found that pre-resection antibiotics targeting anaerobic bacteria substantially improved disease-free survival by 25.5%. For mouse studies, we designed an antibiotic silver-tinidazole complex encapsulated in liposomes (LipoAgTNZ) to eliminate tumor-associated bacteria in the primary tumor and liver metastases without causing gut microbiome dysbiosis. Mouse CRC models colonized by tumor-promoting bacteria ( Fusobacterium nucleatum spp.) or probiotics ( Escherichia coli Nissle spp.) responded to LipoAgTNZ therapy, which enabled more than 70% long-term survival in two F. nucleatum -infected CRC models. The antibiotic treatment generated microbial neoantigens that elicited anti-tumor CD8 + T cells. Heterologous and homologous bacterial epitopes contributed to the immunogenicity, priming T cells to recognize both infected and uninfected tumors. Our strategy targets tumor-associated bacteria to elicit anti-tumoral immunity, paving the way for microbiome–immunotherapy interventions. Killing bacteria in tumors boosts survival in a mouse model of colon cancer.

Generation and subsequently accessibility of secondary findings (SF) in diagnostic practice is a subject of debate around the world and particularly in Europe. The French FIND study has been set up to assess patient/parent expectations regarding SF from exome sequencing (ES) and to collect their real-life experience until 1 year after the delivery of results. 340 patients who had ES for undiagnosed developmental disorders were included in this multicenter mixed study (quantitative N = 340; qualitative N = 26). Three groups of actionable SF were rendered: predisposition to late-onset actionable diseases; genetic counseling; pharmacogenomics. Participants expressed strong interest in obtaining SF and a high satisfaction level when a SF is reported. The medical actionability of the SF reinforced parents’ sense of taking action for their child and was seen as an opportunity. While we observed no serious psychological concerns, we showed that these results could have psychological consequences, in particular for late-onset actionable diseases SF, within families already dealing with rare diseases. This study shows that participants remain in favor of accessing SF despite the potential psychological, care, and lifestyle impacts, which are difficult to anticipate. The establishment of a management protocol, including the support of a multidisciplinary team, would be necessary if national policy allows the reporting of these data.

Madagascar accounts for 75% of global plague cases reported to WHO, with an annual incidence of 200–700 suspected cases (mainly bubonic plague). In 2017, a pneumonic plague epidemic of unusual size occurred. The extent of this epidemic provides a unique opportunity to better understand the epidemiology of pneumonic plagues, particularly in urban settings. Clinically suspected plague cases were notified to the Central Laboratory for Plague at Institut Pasteur de Madagascar (Antananarivo, Madagascar), where biological samples were tested. Based on cases recorded between Aug 1, and Nov 26, 2017, we assessed the epidemiological characteristics of this epidemic. Cases were classified as suspected, probable, or confirmed based on the results of three types of diagnostic tests (rapid diagnostic test, molecular methods, and culture) according to 2006 WHO recommendations. 2414 clinically suspected plague cases were reported, including 1878 (78%) pneumonic plague cases, 395 (16%) bubonic plague cases, one (<1%) septicaemic case, and 140 (6%) cases with unspecified clinical form. 386 (21%) of 1878 notified pneumonic plague cases were probable and 32 (2%) were confirmed. 73 (18%) of 395 notified bubonic plague cases were probable and 66 (17%) were confirmed. The case fatality ratio was higher among confirmed cases (eight [25%] of 32 cases) than probable (27 [8%] of 360 cases) or suspected pneumonic plague cases (74 [5%] of 1358 cases) and a similar trend was seen for bubonic plague cases (16 [24%] of 66 confirmed cases, four [6%] of 68 probable cases, and six [2%] of 243 suspected cases). 351 (84%) of 418 confirmed or probable pneumonic plague cases were concentrated in Antananarivo, the capital city, and Toamasina, the main seaport. All 50 isolated Yersinia pestis strains were susceptible to the tested antibiotics. This predominantly urban plague epidemic was characterised by a large number of notifications in two major urban areas and an unusually high proportion of pneumonic forms, with only 23% having one or more positive laboratory tests. Lessons about clinical and biological diagnosis, case definition, surveillance, and the logistical management of the response identified in this epidemic are crucial to improve the response to future plague outbreaks. US Agency for International Development, WHO, Institut Pasteur, US Department of Health and Human Services, Laboratoire d'Excellence Integrative Biology of Emerging Infectious Diseases, Models of Infectious Disease Agent Study of the National Institute of General Medical Sciences, AXA Research Fund, and the INCEPTION programme.